Pharmacokinetics of retinyl palmitate and retinol after intramuscular retinyl palmitate administration in severe malaria

Abstract

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (< 1.0 µmol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7–15.1 h), a bioavailability of 55% (19–100%) and an elimination half-life of 13.5 h (4.2–23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P < 0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7–15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.